Mirdametinib treatment

ABSTRACT

The present disclosure relates to a method for treating certain types of tumors or cancers, such as plexiform neurofibromas (PN), plexiform neurofibromas associated with neurofibromatosis type 1 (NF1-PN), by orally administering an effective amount of mirdametinib to the patient, where an amount of mirdametinib is administered on the first day of treatment to provide (i) an AUC 0-tau  less than 400 ng·h/mL, (ii) a C max  no more than 40 ng/mL, or (iii) both.

The present application claims the benefit of U.S. ProvisionalApplication Nos. 63/321,036, filed Mar. 17, 2022, and 63/321,046, filedMar. 17, 2022, each of which is hereby incorporated by reference in itsentirety.

FIELD OF THE INVENTION

The present disclosure relates to a method for treating certain types oftumors or cancers, such as plexiform neurofibromas (PN), plexiformneurofibromas associated with neurofibromatosis type 1 (NF1-PN), byorally administering an effective amount of mirdametinib to the patient,where an amount of mirdametinib is administered on the first day oftreatment to provide (i) an AUC_(0-tau) less than 400 ng·h/mL, (ii) aC_(max) no more than 40 ng/mL, or (iii) both.

BACKGROUND

Mirdametinib is an allosteric, small molecule targetingmitogen-activated protein kinase kinase (MEK).

Weiss describes a Phase II clinical trial of mirdametinib in subjectswith neurofibromatosis type 1 who have a plexiform neurofibroma (Weisset al., J. Clin. Oncol., 29, 797-806, 2021).

There is a continuing need for improved treatments for tumors andcancers, including NF1-PN.

BRIEF SUMMARY OF THE INVENTION

One aspect of the present invention relates to a method of treating apatient (e.g., a human patient) 2 years or older who hasneurofibromatosis type 1 (NF1) associated inoperable plexiformneurofibromas (PN) by orally administering an effective amount ofmirdametinib to the patient, where an amount of mirdametinib isadministered on the first day of treatment to provide an AUC_(0-tau)less than 400 ng·h/mL. It has been discovered that lower amounts ofmirdametinib may be administered to effectively treat patients having atumor or cancer, such as NF1-PN, with reduced toxicity. In oneembodiment, the patient continues to be administered the mirdametinib toprovide an AUC_(0-tau) less than 400 ng·h/mL. In one embodiment, thepatient has symptomatic, inoperable plexiform neurofibromas.

Another embodiment is a method of treating a patient 2 years or olderwho has NF1 associated inoperable PN that is progressing or causingsignificant morbidity by orally administering an effective amount ofmirdametinib to the patient, where an amount of mirdametinib isadministered on the first day of treatment to provide an AUC_(0-tau)less than 400 ng·h/mL. In one embodiment, the patient continues to beadministered the mirdametinib to provide an AUC_(0-tau) less than 400ng·h/mL.

Yet another embodiment is a method of treating a human patient 2 yearsor older who has neurofibromatosis type 1 (NF1) associated inoperableplexiform neurofibromas (PN) by orally administering on the first day oftreatment 1 mg of mirdametinib twice daily to the patient to achieve anAUC_(0-tau) less than 400 ng·h/mL.

Yet another embodiment is a method of treating a human patient 2 yearsor older who has neurofibromatosis type 1 (NF1) associated inoperableplexiform neurofibromas (PN) comprising orally administering on thefirst day of treatment 1 mg of mirdametinib twice daily to the patientto provide a C_(max) no more than 40 ng/mL.

Yet another embodiment is a method of treating a human patient 8 yearsor older who has neurofibromatosis type 1 (NF1) associated inoperableplexiform neurofibromas (PN) comprising orally administering aneffective amount of mirdametinib to the patient, wherein an amount ofmirdametinib is administered on the first day of treatment to provide(i) an AUC_(0-tau) less than 400 ng·h/mL, (ii) a C_(max) no more than 40ng/mL, or (iii) both, wherein, during treatment, the patient suffersfrom acneiform rash and is topically treated (or administered) withclindamycin. In one embodiment, the patient suffers from pustular rash.In one embodiment, the patient continues to be administered themirdametinib to provide an AUC_(0-tau) less than 400 ng·h/mL.

Yet another embodiment is a method of treating a tumor or cancer in apatient (e.g., a human patient) by orally administering an effectiveamount of mirdametinib to the patient, wherein an amount of mirdametinibis administered on the first day of treatment to provide (i) anAUC_(0-tau) less than 400 ng·h/mL, (ii) a C_(max) no more than 40 ng/mL,or (iii) both. In one embodiment, the patient continues to beadministered the mirdametinib to provide (i) an AUC_(0-tau) less than400 ng·h/mL, (ii) a C_(max) no more than 40 ng/mL, or (iii) both. In oneembodiment, the tumor or cancer is selected from the group consisting ofplexiform neurofibromas (PN), plexiform neurofibromas associated withneurofibromatosis type 1 (NF1-PN), high grade glioma (HGG), low gradeovarian cancer, Langerhans cell histiocytosis (LCH), brain cancer, and acancer that has metastasized to a patient's brain. In one embodiment,the tumor or cancer is plexiform neurofibromas. In another embodiment,the tumor or cancer is plexiform neurofibromas associated withneurofibromatosis type 1. In yet another embodiment, the tumor or canceris high grade glioma. In yet another embodiment, the high grade gliomais a primary cancer. In yet another embodiment, the high grade glioma isa metastatic cancer. In yet another embodiment, the tumor or cancer islow grade ovarian cancer. In yet another embodiment, the tumor or canceris Langerhans cell histiocytosis. In yet another embodiment, the tumoror cancer is brain cancer. In yet another embodiment, the tumor orcancer is a cancer that has metastasized to the patient's brainincluding lung cancer, breast cancer and melanoma.

Yet another embodiment is a method of treating a human patient 2 yearsor older who has neurofibromatosis type 1 (NF1) associated inoperableplexiform neurofibromas (PN) by orally administering an effective amountof mirdametinib to the patient, where an amount of mirdametinib isadministered on the first day of treatment to provide a C_(max) no morethan 40 ng/mL.

Yet another embodiment is a method of treating a human patient 2 yearsor older who has neurofibromatosis type 1 (NF1) associated inoperableplexiform neurofibromas (PN) that is progressing or causing significantmorbidity by orally administering an effective amount of mirdametinib tothe patient, where an amount of mirdametinib is administered on thefirst day of treatment to provide a C_(max) no more than 40 ng/mL. Inone embodiment, an amount of mirdametinib is administered on the firstday of treatment to provide a C_(max) no more than 32 ng/mL. In anotherembodiment, an amount of mirdametinib is administered on the first dayof treatment to provide a C_(max) no more than 30 ng/mL.

Yet another embodiment is a method of treating a human patient at least2 years of age who has neurofibromatosis type 1 (NF1) associatedinoperable plexiform neurofibromas (PN) comprising

-   -   (a) selecting mirdametinib as a treatment for the patient at        least partially based on its objective response rate, where the        objective response rate is defined as at least a 20% decrease in        tumor size using centrally read MRI volumetric analysis, and    -   (b) upon selection of mirdametinib as a treatment, orally        administering an effective amount of mirdametinib to the        patient. In one embodiment, in step (a), mirdametinib is        selected based on a response rate of at least 70%. In another        embodiment, in step (i), mirdametinib is selected based on a        response rate of at least 75%. In yet another embodiment, in        step (i), mirdametinib is selected based on a response rate of        at least 80%. In yet another embodiment, in step (i),        mirdametinib is selected based on a response rate of at least        85%. In yet another embodiment, in step (i), mirdametinib is        selected based on a response rate of at least 90%. In yet        another embodiment, in step (i), mirdametinib is selected based        on a response rate of at least 95%.

In one embodiment of any of the methods described herein, an amount ofmirdametinib is administered on the first day of treatment to provide anAUC_(0-tau) less than 200 ng·h/mL. In one embodiment, the patientcontinues to be administered the mirdametinib to provide an AUC_(0-tau)less than 200 ng·h/mL.

In one embodiment of any of the methods described herein, an amount ofmirdametinib is administered on the first day of treatment to provide anAUC_(0-tau) less than 100 ng·h/mL. In one embodiment, the patientcontinues to be administered the mirdametinib to provide an AUC_(0-tau)less than 100 ng·h/mL.

In one embodiment of any of the methods described herein, the patienthas symptomatic, inoperable plexiform neurofibromas (PNs).

In one embodiment of any of the methods described herein, the patienthas progressive PN.

In one embodiment of any of the methods described herein, the patienthas PNs that cause significant morbidity.

In one embodiment of any of the methods described herein, the patient(e.g., NF1-PN patient) has head and neck lesions that are compromisingthe airway or great vessels, brachial or lumbar plexus lesions that arecausing nerve compression and loss of function, lesions causing majordeformity or are significantly disfiguring, lesions of the extremitythat cause limb hypertrophy or loss of function, or painful lesions. Inone embodiment, the lesions causing major deformity or are significantlydisfiguring are tumors of the head and neck or those on other areas ofthe body that are unable to be concealed by standard garments. In oneembodiment of any of the methods described herein, the patient hasparaspinal lesions.

In one embodiment of any of the methods described herein, the patienthas the clinical diagnosis of NF1 using the NIH Consensus Conference andone or more of the following:

-   -   (a) six or more café-au-lait macules with a diameter >5 mm in        prepubertal and >15 mm in post-pubertal individuals;    -   (b) freckling in axilla or inguinal regions;    -   (c) optic glioma;    -   (d) two or more Lisch nodules;    -   (e) a distinctive bony lesion (dysplasia of the sphenoid bone or        dysplasia of thinning of long bone cortex); and    -   (f) a first degree relative with NF1.

In one embodiment of any of the methods described herein, the patienthas a constitutional NF1 mutation documented in a Clinical LaboratoryImprovement Amendments/College of American Pathologists certified lab.

In one embodiment of any of the methods described herein, the patienteither (a) has a parent diagnosed with NF1 and one or more criteria of(1) through (7) or (b) does not have a parent diagnosed with NF1 but hastwo or more criteria of (1) through (7):

-   -   (1) six or more café-au-lait macules over 5 mm in greatest        diameter in prepubertal individuals and over 15 mm in greatest        diameter in post-pubertal individuals;    -   (2) freckling in the axillary or inguinal region;    -   (3) two or more neurofibromas of any type or one plexiform        neurofibroma    -   (4) optic pathway glioma;    -   (5) two or more iris Lisch nodules identified by slit lamp        examination or two or more choroidal abnormalities (defined as        bright, patchy nodules imaged by optical coherence tomography        (OCT)/near-infrared reflectance (NIR) imaging;    -   (6) a distinctive osseus lesion (such as sphenoid dysplasia,        anterolateral bowing of the tibia, or pseudarthrosis of a long        bone); and    -   (7) a heterozygous pathogenic NF1 variant with a variant allele        fraction of 50% in apparently normal tissue such as white blood        cells.

In one embodiment of any of the methods described herein,

-   -   (a) for a patient having a body surface area no more than 0.69        m², the patient is initially administered 1 mg mirdametinib        twice daily,    -   (b) for a patient having a body surface area of 0.7 to 1.04 m²,        the patient is initially administered 2 mg mirdametinib twice        daily,    -   (c) for a patient having a body surface area of 1.05 to 1.49 m²,        the patient is initially administered 3 mg mirdametinib twice        daily, and    -   (d) for a patient having a body surface area of at least 1.5 m²,        the patient is initially administered 4 mg mirdametinib twice        daily.

In one embodiment of any of the methods described herein, the initialdosage regimen is continued to be used, unless for instance, a severeadverse event occurs requiring reduction in the dosage regimen.

In one embodiment of any of the methods described herein, the maximumdaily dose is 4 mg mirdametinib twice daily.

In one embodiment of any of the methods described herein, over each fourweek period, the mirdametinib is administered for the first three weeksand discontinued for the last one week.

In one embodiment of any of the methods described herein, the patienthas at least a 20% reduction in plexiform neurofibroma volume asdetermined by volumetric magnetic resonance imaging analysis followingtreatment with mirdametinib.

In one embodiment of any of the methods described herein, the treatmentresults in decreased pain intensity.

In one embodiment of any of the methods described herein, the treatmentresults in decreased pain interference.

In one embodiment of any of the methods described herein, the doseadministered is reduced due to an adverse event, wherein the dose isreduced as follows:

-   -   (a) if the dose at the time of the event is 1 mg mirdametinib        twice daily, then the reduced daily dose is 1 mg administered in        the morning only;    -   (b) if the dose at the time of the event is 2 mg mirdametinib        twice daily, then the reduced daily dose is 2 mg administered in        the morning and 1 mg administered in the afternoon or evening;    -   (c) if the dose at the time of the event is 3 mg mirdametinib        twice daily, then the reduced daily dose is 2 mg administered        twice daily; and    -   (d) if the dose at the time of the event is 4 mg mirdametinib        twice daily, then the reduced daily dose is 3 mg administered        twice daily. In one embodiment, the adverse event resulting in        the dose reduction is acneiform.

In one embodiment of any of the methods described herein, duringtreatment, the patient is topically administered clindamycin to treatthe acneiform.

In one embodiment of any of the methods described herein, the patient isat least 2 years of age. In one embodiment, the patient has an age of ≥2and <25. In yet another embodiment of any of the methods describedherein, the patient is 2 to 15 years of age.

In one embodiment of any of the methods described herein, the methodfurther comprises prior to treatment (i) determining whether to selectmirdametinib as a treatment for the patient, and (ii) selectingmirdametinib as a treatment for the patient at least partially based onits objective response rate, where the objective response rate isdefined as at least a 20% decrease in tumor size using centrally readMRI volumetric analysis. In one embodiment, in step (i), mirdametinib isselected based on a response rate of at least 70%. In anotherembodiment, in step (i), mirdametinib is selected based on a responserate of at least 75%. In yet another embodiment, in step (i),mirdametinib is selected based on a response rate of at least 80%. Inyet another embodiment, in step (i), mirdametinib is selected based on aresponse rate of at least 85%. In yet another embodiment, in step (i),mirdametinib is selected based on a response rate of at least 90%. Inyet another embodiment, in step (i), mirdametinib is selected based on aresponse rate of at least 95%.

In some aspects, a therapeutically effective amount of mirdametinib, ora pharmaceutically acceptable salt thereof, is administered. In someaspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in an amount of about 1 mg/m² to about 10 mg/m²per day based on mirdametinib free base. In some aspects, themirdametinib, or a pharmaceutically acceptable salt thereof, isadministered in an amount of about 1 mg to about 10 mg per day based onmirdametinib free base.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in a single dosage form comprising about 0.1mg/m² to about 10 mg/m² based on mirdametinib free base. In someaspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in a single dosage form comprising about 0.1 mgto about 10 mg based on mirdametinib free base.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered once daily. In some aspects, the mirdametinib,or a pharmaceutically acceptable salt thereof, is administered twicedaily.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, exhibits high blood-brain-barrier penetration.

In one embodiment of any of the methods described herein, the humanpatient has had no prior exposure to MEK inhibitors.

In one embodiment of any of the methods described herein, themirdametinib, or a pharmaceutically acceptable salt thereof, isadministered orally. In some aspects, the mirdametinib, or apharmaceutically acceptable salt thereof, is dispersible in a potableliquid or orodispersible in a patient's saliva. In some aspects, themirdametinib, or a pharmaceutically acceptable salt thereof, isadministered orally as a solid dosage form. In some aspects, the soliddosage form is a tablet or capsule. In some aspects, the solid dosageform is a capsule.

In one embodiment of any of the methods described herein, themirdametinib, or a pharmaceutically acceptable salt thereof, isadministered as a monotherapy to treat the tumor or cancer. In someaspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in combination with another active ingredientand/or surgery to treat the tumor or cancer.

In one embodiment of any of the methods described herein, themirdametinib is mirdametinib free base.

Yet another embodiment is an oral pharmaceutical composition comprising1 mg mirdametinib, where the composition provides, upon initial oraladministration to a human subject who has just initiated treatment withmirdametinib, an AUC_(0-tau) less than 400 ng·h/mL. In one embodiment,the composition provides, upon initial oral administration to a humansubject who has just initiated treatment with mirdametinib, anAUC_(0-tau) less than 375, 350, 325, 300, 275, 250, 225, 200, 175, 150,125, or 100 ng·h/mL.

Yet another embodiment is an oral pharmaceutical composition comprising1 mg mirdametinib, where the composition provides, upon initial oraladministration to a human subject who has just initiated treatment withmirdametinib, a C_(max) no more than 40 ng/mL. In one embodiment, thecomposition provides, upon initial oral administration to a humansubject who has just initiated treatment with mirdametinib, a C_(max) nomore than 38, 36, 34, 32, 30, or 28 ng/mL.

In one embodiment of any of the compositions described herein, themirdametinib is mirdametinib free base.

DETAILED DESCRIPTION OF THE INVENTION Definitions

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures inorganic chemistry, medicinal chemistry, and pharmacology describedherein are those well-known and commonly employed in the art. Unlessdefined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this disclosure belongs.

In this specification and the appended claims, the singular forms “a,”“an” and “the” include plural referents unless the context clearlydictates otherwise. The terms “a” (or “an”), as well as the terms “oneor more,” and “at least one” can be used interchangeably herein. Incertain aspects, the term “a” or “an” means “single.” In other aspects,the term “a” or “an” includes “two or more” or “multiple.”

Furthermore, “and/or” where used herein is to be taken as specificdisclosure of each of the two specified features or components with orwithout the other. Thus, the term “and/or” as used in a phrase such as“A and/or B” herein is intended to include “A and B,” “A or B,” “A”(alone), and “B” (alone). Likewise, the term “and/or” as used in aphrase such as “A, B, and/or C” is intended to encompass each of thefollowing aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; Aand C; A and B; B and C; A (alone); B (alone); and C (alone).

The term “mirdametinib” refers to the single enantiomerN-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.The teachings throughout the specification regarding mirdametinibequally apply to pharmaceutically acceptable salts of mirdametinib. Forinstance, the disclosure of a method of treating neurofibromatosis type1 (NF1) associated inoperable plexiform neurofibromas (PN) withmirdametinib also means that a pharmaceutically acceptable salt ofmirdametinib can be administered to treat NF1 associated inoperable PN.

The term “mg/m²” refers to the dose in milligrams per m² body surfacearea of the patient.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat,or mouse. The terms “subject” and “patient” are used interchangeablyherein in reference, for example, to a mammalian subject, such as ahuman subject. The patient may be a pediatric patient.

The term “pediatric” refers to a human subject under the age of 21 yearsat the time of treatment. The term “pediatric” can be further dividedinto various subpopulations including: neonates (from birth through thefirst 28 days of life); infants (29 days of age to less than two yearsof age); children (two years of age to less than 12 years of age); andadolescents (12 years of age through 21 years of age (up to, but notincluding, the twenty-second birthday)). See, e.g., Berhman R E,Kliegman R, Arvin A M, Nelson W E. Nelson Textbook of Pediatrics, 15thEd. Philadelphia: W. B. Saunders Company, 1996; Rudolph A M, et al.Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First L R. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins;1994. Younger pediatric patients in particular, such as neonates,infants and young children, can have difficulty swallowing wholecapsules or tablets.

The term “AUC_(0-tau)” refers to the area under the plasmaconcentration-time curve from time 0 to the end of the dosing interval.For a twice daily drug, the dosing interval would be 0-12 hours.

The term “C_(max)” refers to the maximum plasma concentration.

The term “dispersible” as used herein refers to a composition (e.g., atablet, powder, granules, minitablets, or pellets) which disintegratesand/or dissolves when combined with water or another potable liquid(e.g., a non-water beverage), or a subject's own saliva when placed inthe subject's mouth, with or without the addition of agitation ortemperature modification. In some aspects, the dispersible compositiondisintegrates or dissolves within 10 minutes, 9 minutes, 8 minutes, 7minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1minute after being combined with water or another potable liquid. Suchdisintegration or dissolution need not be complete. For example, adispersible tablet may dissolve almost entirely, but some undissolvedparticulate matter may remain.

The term “orodispersible” refers to a composition which is capable ofdissolving or disintegrating in a subject's mouth (i.e., dissolving ordisintegrating in a subject's saliva) if administered orally, without arequirement of first dissolving or disintegrating in a separatecontainer.

As used herein, the terms “treat,” “treated,” and “treating” mean boththerapeutic treatment and prophylactic or preventative measures whereinthe object is to prevent or slow down (lessen) an undesiredphysiological condition, disorder, or disease, or obtain beneficial ordesired clinical results. Thus, those in need of treatment include thosealready diagnosed with or suspected of having the disorder. Beneficialor desired clinical results include, but are not limited to, alleviationof symptoms; diminishment of the extent of a condition, disorder, ordisease; stabilized (i.e., not worsening) state of condition, disorder,or disease; delay in onset or slowing of condition, disorder, or diseaseprogression; amelioration of the condition, disorder, or disease stateor remission (whether partial or total), whether detectable orundetectable; an amelioration of at least one measurable physicalparameter, not necessarily discernible by the patient; or enhancement orimprovement of condition, disorder, or disease. Treatment includeseliciting a clinically significant response without excessive levels ofside effects. Treatment also includes prolonging survival as compared toexpected survival if not receiving treatment. The term “therapeuticallyeffective amount” is meant to include the amount of a compound that,when administered, is sufficient to prevent development of, or alleviateto some extent, one or more of the symptoms of a disorder, disease, orcondition being treated. The term “therapeutically effective amount”also refers to the amount of a compound that is sufficient to elicit thebiological or medical response of a cell, tissue, system, animal, orhuman, which is being sought by a researcher, veterinarian, medicaldoctor, or clinician.

In certain aspects, a subject is successfully “treated” for a tumor,according to the methods described herein if the patient shows one ormore of the following: a reduction in the size of the tumor; relief ofone or more symptoms associated with the specific tumor; a reduction inthe volume of the tumor; improvement in quality of life; increasedprogression-free survival (PFS), disease-free survival (DFS), overallsurvival (OS), metastasis-free survival (MFS), complete response (CR),minimal residual disease (MRD), partial response (PR), stable disease(SD), a decrease in progressive disease (PD), an increased time toprogression (TTP), or any combination thereof. In some aspects,nationally or internationally accepted standards of treatment outcomesin a given tumor can be used to determine whether an effective amount ofmirdametinib meets any of these particular endpoints (e.g., CR, PFS,PR).

In certain aspects, a subject is successfully “treated” for cancer,e.g., ovarian cancer, according to the methods described herein if thepatient shows one or more of the following: a reduction in the number ofor complete absence of cancer cells; relief of one or more symptomsassociated with the specific cancer; reduced morbidity and mortality;improvement in quality of life; increased progression-free survival(PFS), disease-free survival (DFS), overall survival (OS),metastasis-free survival (MFS), complete response (CR), minimal residualdisease (MRD), partial response (PR), stable disease (SD), a decrease inprogressive disease (PD), an increased time to progression (TTP), or anycombination thereof. In some aspects, nationally or internationallyaccepted standards of treatment outcomes in a given cancer can be usedto determine whether an effective amount of mirdametinib meets any ofthese particular endpoints (e.g., CR, PFS, PR).

The terms “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refer to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, excipient, solvent, or encapsulatingmaterial. In one embodiment, each component is “pharmaceuticallyacceptable” in the sense of being compatible with the other ingredientsof a pharmaceutical formulation, and suitable for use in contact withthe tissue or organ of humans and animals without excessive toxicity,irritation, allergic response, immunogenicity, or other problems orcomplications, commensurate with a reasonable benefit/risk ratio. SeeRemington: The Science and Practice of Pharmacy, 21st Edition,Lippincott Williams & Wilkins: Philadelphia, P A, 2005; Handbook ofPharmaceutical Excipients, 5th Edition, Rowe et al., Eds., ThePharmaceutical Press and the American Pharmaceutical Association: 2005;and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds.,Gower Publishing Company: 2007; Pharmaceutical Preformulation andFormulation, Gibson Ed., CRC Press LLC: Boca Raton, F L, 2004(incorporated herein by reference).

The term “pharmaceutically-acceptable salts” refers to the relativelynontoxic, inorganic and organic acid addition salts of mirdametinib.These salts can be prepared in situ in the administration vehicle or thedosage form manufacturing process, or by separately reacting a purifiedcompound of the invention in its free base form with a suitable organicor inorganic acid, and isolating the salt thus formed during subsequentpurification. Representative salts include the hydrobromide,hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate,valerate, oleate, palmitate, stearate, laurate, benzoate, lactate,phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate,napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonatesalts. See, e.g., Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm.Sci. 66:1-19.

The pharmaceutically acceptable salts of the subject compounds includethe conventional nontoxic salts or quaternary ammonium salts of thecompounds, e.g., from nontoxic organic or inorganic acids. For example,such conventional nontoxic salts include those derived from inorganicacids such as hydrochloride, hydrobromic, sulfuric, sulfamic,phosphoric, and nitric acid; and the salts prepared from organic acidssuch as acetic, propionic, succinic, glycolic, stearic, lactic, malic,tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicyclic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, and isothionic.

The terms “about” or “approximately” means an acceptable error for aparticular value as determined by one of ordinary skill in the art,which depends in part on how the value is measured or determined. Incertain embodiments, the term “about” or “approximately” means within 1,2, 3, or 4 standard deviations. In certain embodiments, the term “about”or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

Unless the context requires otherwise, the terms “comprise,”“comprises,” and “comprising” are used on the basis and clearunderstanding that they are to be interpreted inclusively, rather thanexclusively, and that Applicant intends each of those words to be sointerpreted in construing this patent, including the claims below.

II. Methods of Treatment

One aspect of the present invention relates to a method of treating apatient (e.g., a human patient) 2 years or older who hasneurofibromatosis type 1 (NF1) associated inoperable plexiformneurofibromas (PN) by orally administering an effective amount ofmirdametinib to the patient, where an amount of mirdametinib isadministered on the first day of treatment to provide an AUC_(0-tau)less than 400 ng·h/mL. In one embodiment, the patient continues to beadministered the mirdametinib to provide an AUC_(0-tau) less than 400ng·h/mL. In one embodiment, the patient has symptomatic, inoperableplexiform neurofibromas.

Another embodiment is a method of treating a patient 2 years or olderwho has NF1 associated inoperable PN that is progressing or causingsignificant morbidity by orally administering an effective amount ofmirdametinib to the patient, where an amount of mirdametinib isadministered on the first day of treatment to provide an AUC_(0-tau)less than 400 ng·h/mL. In one embodiment, the patient continues to beadministered the mirdametinib to provide an AUC_(0-tau) less than 400ng·h/mL.

Yet another embodiment is a method of treating a human patient 2 yearsor older who has neurofibromatosis type 1 (NF1) associated inoperableplexiform neurofibromas (PN) by orally administering on the first day oftreatment 1 mg of mirdametinib twice daily to the patient to achieve anAUC_(0-tau) less than 400 ng·h/mL.

Yet another embodiment is a method of treating a human patient 2 yearsor older who has neurofibromatosis type 1 (NF1) associated inoperableplexiform neurofibromas (PN) comprising orally administering on thefirst day of treatment 1 mg of mirdametinib twice daily to the patientto provide a C_(max) no more than 40 ng/mL.

Yet another embodiment is a method of treating a human patient 8 yearsor older who has neurofibromatosis type 1 (NF1) associated inoperableplexiform neurofibromas (PN) comprising orally administering aneffective amount of mirdametinib to the patient, wherein an amount ofmirdametinib is administered on the first day of treatment to provide(i) an AUC_(0-tau) less than 400 ng·h/mL, (ii) a C_(max) no more than 40ng/mL, or (iii) both, wherein, during treatment, the patient suffersfrom acneiform rash and is topically treated (or administered) withclindamycin. In one embodiment, the patient suffers from pustular rash.In one embodiment, the patient continues to be administered themirdametinib to provide an AUC_(0-tau) less than 400 ng·h/mL.

Yet another embodiment is a method of treating a tumor or cancer in apatient (e.g., a human patient) by orally administering an effectiveamount of mirdametinib to the patient, wherein an amount of mirdametinibis administered on the first day of treatment to provide (i) anAUC_(0-tau) less than 400 ng·h/mL, (ii) a C_(max) no more than 40 ng/mL,or (iii) both. In one embodiment, the patient continues to beadministered the mirdametinib to provide (i) an AUC_(0-tau) less than400 ng·h/mL, (ii) a C_(max) no more than 40 ng/mL, or (iii) both. In oneembodiment, the tumor or cancer is selected from the group consisting ofplexiform neurofibromas (PN), plexiform neurofibromas associated withneurofibromatosis type 1 (NF1-PN), high grade glioma (HGG), low gradeovarian cancer, Langerhans cell histiocytosis (LCH), brain cancer, and acancer that has metastasized to a patient's brain. In one embodiment,the tumor or cancer is plexiform neurofibromas. In another embodiment,the tumor or cancer is plexiform neurofibromas associated withneurofibromatosis type 1. In yet another embodiment, the tumor or canceris high grade glioma. In yet another embodiment, the high grade gliomais a primary cancer. In yet another embodiment, the high grade glioma isa metastatic cancer. In yet another embodiment, the tumor or cancer islow grade ovarian cancer. In yet another embodiment, the tumor or canceris Langerhans cell histiocytosis. In yet another embodiment, the tumoror cancer is brain cancer. In yet another embodiment, the tumor orcancer is a cancer that has metastasized to the patient's brainincluding lung cancer, breast cancer and melanoma.

Yet another embodiment is a method of treating a human patient 2 yearsor older who has neurofibromatosis type 1 (NF1) associated inoperableplexiform neurofibromas (PN) by orally administering an effective amountof mirdametinib to the patient, where an amount of mirdametinib isadministered on the first day of treatment to provide a C_(max) no morethan 40 ng/mL.

Yet another embodiment is a method of treating a human patient 2 yearsor older who has neurofibromatosis type 1 (NF1) associated inoperableplexiform neurofibromas (PN) that is progressing or causing significantmorbidity by orally administering an effective amount of mirdametinib tothe patient, where an amount of mirdametinib is administered on thefirst day of treatment to provide a C_(max) no more than 40 ng/mL. Inone embodiment, an amount of mirdametinib is administered on the firstday of treatment to provide a C_(max) no more than 32 ng/mL. In anotherembodiment, an amount of mirdametinib is administered on the first dayof treatment to provide a C_(max) no more than 30 ng/mL.

Yet another embodiment is a method of treating a human patient at least2 years of age who has neurofibromatosis type 1 (NF1) associatedinoperable plexiform neurofibromas (PN) comprising

-   -   (a) selecting mirdametinib as a treatment for the patient at        least partially based on its objective response rate, where the        objective response rate is defined as at least a 20% decrease in        tumor size using centrally read MRI volumetric analysis, and    -   (b) upon selection of mirdametinib as a treatment, orally        administering an effective amount of mirdametinib to the        patient. In one embodiment, in step (a), mirdametinib is        selected based on a response rate of at least 70%. In another        embodiment, in step (i), mirdametinib is selected based on a        response rate of at least 75%. In yet another embodiment, in        step (i), mirdametinib is selected based on a response rate of        at least 80%. In yet another embodiment, in step (i),        mirdametinib is selected based on a response rate of at least        85%. In yet another embodiment, in step (i), mirdametinib is        selected based on a response rate of at least 90%. In yet        another embodiment, in step (i), mirdametinib is selected based        on a response rate of at least 95%.

In one embodiment of any of the methods described herein, an amount ofmirdametinib is administered on the first day of treatment to provide anAUC_(0-tau) less than 375, 350, 325, 300, 275, 250, 225, 200, 175, 150,125, or 100 ng·h/mL. In one embodiment, the patient continues to beadministered the mirdametinib to provide an AUC_(0-tau) less than 375,350, 325, 300, 275, 250, 225, 200, 175, 150, 125, or 100 ng·h/mL.

In one embodiment of any of the methods described herein, an amount ofmirdametinib is administered on the first day of treatment to provide anAUC_(0-tau) less than 200 ng·h/mL. In one embodiment, the patientcontinues to be administered the mirdametinib to provide an AUC_(0-tau)less than 200 ng·h/mL.

In one embodiment of any of the methods described herein, an amount ofmirdametinib is administered on the first day of treatment to provide anAUC_(0-tau) less than 100 ng·h/mL. In one embodiment, the patientcontinues to be administered the mirdametinib to provide an AUC_(0-tau)less than 100 ng·h/mL.

In one embodiment of any of the methods described herein, an amount ofmirdametinib is administered on the first day of treatment to provide aC_(max) no more than 38, 36, 34, 32, 30, or 28 ng/mL. In anotherembodiment of any of the methods described herein, an amount ofmirdametinib is administered on the first day of treatment to provide aC_(max) no more than 32 ng/mL. In yet another embodiment, an amount ofmirdametinib is administered on the first day of treatment to provide aC_(max) no more than 30 ng/mL.

In one embodiment of any of the methods described herein, the patienthas symptomatic, inoperable plexiform neurofibromas (PNs).

In one embodiment of any of the methods described herein, the patienthas progressive PN.

In one embodiment of any of the methods described herein, the patienthas PNs that cause significant morbidity.

In one embodiment of any of the methods described herein, the patient(e.g., NF1-PN patient) has head and neck lesions that are compromisingthe airway or great vessels, brachial or lumbar plexus lesions that arecausing nerve compression and loss of function, lesions causing majordeformity or are significantly disfiguring, lesions of the extremitythat cause limb hypertrophy or loss of function, or painful lesions. Inone embodiment, the lesions causing major deformity or are significantlydisfiguring are tumors of the head and neck or those on other areas ofthe body that are unable to be concealed by standard garments. In oneembodiment of any of the methods described herein, the patient hasparaspinal lesions.

In one embodiment of any of the methods described herein, the patienthas the clinical diagnosis of NF1 using the NIH Consensus Conference andone or more of the following:

-   -   (a) six or more café-au-lait macules with a diameter >5 mm in        prepubertal and >15 mm in post-pubertal individuals;    -   (b) freckling in axilla or inguinal regions;    -   (c) optic glioma;    -   (d) two or more Lisch nodules;    -   (e) a distinctive bony lesion (dysplasia of the sphenoid bone or        dysplasia of thinning of long bone cortex); and    -   (f) a first degree relative with NF1.

In one embodiment of any of the methods described herein, the patienthas a constitutional NF1 mutation documented in a Clinical LaboratoryImprovement Amendments/College of American Pathologists certified lab.

In one embodiment of any of the methods described herein, the patienteither (a) has a parent diagnosed with NF1 and one or more criteria of(1) through (7) or (b) does not have a parent diagnosed with NF1 but hastwo or more criteria of (1) through (7):

-   -   (1) six or more café-au-lait macules over 5 mm in greatest        diameter in prepubertal individuals and over 15 mm in greatest        diameter in post-pubertal individuals;    -   (2) freckling in the axillary or inguinal region;    -   (3) two or more neurofibromas of any type or one plexiform        neurofibroma    -   (4) optic pathway glioma;    -   (5) two or more iris Lisch nodules identified by slit lamp        examination or two or more choroidal abnormalities (defined as        bright, patchy nodules imaged by optical coherence tomography        (OCT)/near-infrared reflectance (NIR) imaging;    -   (6) a distinctive osseus lesion (such as sphenoid dysplasia,        anterolateral bowing of the tibia, or pseudarthrosis of a long        bone); and    -   (7) a heterozygous pathogenic NF1 variant with a variant allele        fraction of 50% in apparently normal tissue such as white blood        cells.

In one embodiment of any of the methods described herein,

-   -   (a) for a patient having a body surface area no more than 0.69        m², the patient is initially administered 1 mg mirdametinib        twice daily,    -   (b) for a patient having a body surface area of 0.7 to 1.04 m²,        the patient is initially administered 2 mg mirdametinib twice        daily,    -   (c) for a patient having a body surface area of 1.05 to 1.49 m²,        the patient is initially administered 3 mg mirdametinib twice        daily, and    -   (d) for a patient having a body surface area of at least 1.5 m²,        the patient is initially administered 4 mg mirdametinib twice        daily.

In one embodiment of any of the methods described herein, the initialdosage regimen is continued to be used, unless for instance, a severeadverse event occurs requiring reduction in the dosage regimen.

In one embodiment of any of the methods described herein, the maximumdaily dose is 4 mg mirdametinib twice daily.

In one embodiment of any of the methods described herein, over each fourweek period, the mirdametinib is administered for the first three weeksand discontinued for the last one week.

In one embodiment of any of the methods described herein, the patienthas at least a 20% reduction in plexiform neurofibroma volume asdetermined by volumetric magnetic resonance imaging analysis followingtreatment with mirdametinib.

In one embodiment of any of the methods described herein, the treatmentresults in decreased pain intensity.

In one embodiment of any of the methods described herein, the treatmentresults in decreased pain interference.

In one embodiment of any of the methods described herein, the doseadministered is reduced due to an adverse event, wherein the dose isreduced as follows:

-   -   (a) if the dose at the time of the event is 1 mg mirdametinib        twice daily, then the reduced daily dose is 1 mg administered in        the morning only;    -   (b) if the dose at the time of the event is 2 mg mirdametinib        twice daily, then the reduced daily dose is 2 mg administered in        the morning and 1 mg administered in the afternoon or evening;    -   (c) if the dose at the time of the event is 3 mg mirdametinib        twice daily, then the reduced daily dose is 2 mg administered        twice daily; and    -   (d) if the dose at the time of the event is 4 mg mirdametinib        twice daily, then the reduced daily dose is 3 mg administered        twice daily. In one embodiment, the adverse event resulting in        the dose reduction is acneiform.

In one embodiment of any of the methods described herein, duringtreatment, the patient is topically administered clindamycin to treatthe acneiform.

In one embodiment of any of the methods described herein, the humanpatient is at least 2 years of age. In one embodiment, the human patienthas an age of ≥2 and <25. In yet another embodiment of any of themethods described herein, the human patient is 2 to 15 years of age. Inyet another embodiment of any of the methods described herein, the humanpatient has an age of ≥2 and 18 years.

In one embodiment of any of the methods described herein, the methodfurther comprises prior to treatment (i) determining whether to selectmirdametinib as a treatment for the patient, and (ii) selectingmirdametinib as a treatment for the patient at least partially based onits objective response rate, where the objective response rate isdefined as at least a 20% decrease in tumor size using centrally readMRI volumetric analysis. In one embodiment, in step (i), mirdametinib isselected based on a response rate of at least 70%. In anotherembodiment, in step (i), mirdametinib is selected based on a responserate of at least 75%. In yet another embodiment, in step (i),mirdametinib is selected based on a response rate of at least 80%. Inyet another embodiment, in step (i), mirdametinib is selected based on aresponse rate of at least 85%. In yet another embodiment, in step (i),mirdametinib is selected based on a response rate of at least 90%. Inyet another embodiment, in step (i), mirdametinib is selected based on aresponse rate of at least 95%.

In some aspects, a therapeutically effective amount of mirdametinib, ora pharmaceutically acceptable salt thereof, is administered. In someaspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in an amount of about 1 mg/m² to about 10 mg/m²per day based on mirdametinib free base. In some aspects, themirdametinib, or a pharmaceutically acceptable salt thereof, isadministered in an amount of about 1 mg to about 10 mg per day based onmirdametinib free base.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in a single dosage form comprising about 0.1mg/m² to about 10 mg/m² based on mirdametinib free base. In someaspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in a single dosage form comprising about 0.1 mgto about 10 mg based on mirdametinib free base.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered once daily. In some aspects, the mirdametinib,or a pharmaceutically acceptable salt thereof, is administered twicedaily.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, exhibits high blood-brain-barrier penetration.

In one embodiment of any of the methods described herein, the humanpatient has had no prior exposure to MEK inhibitors.

In one embodiment of any of the methods described herein, themirdametinib, or a pharmaceutically acceptable salt thereof, isadministered orally. In some aspects, the mirdametinib, or apharmaceutically acceptable salt thereof, is dispersible in a potableliquid or orodispersible in a patient's saliva. In some aspects, themirdametinib, or a pharmaceutically acceptable salt thereof, isadministered orally as a solid dosage form. In some aspects, the soliddosage form is a tablet or capsule. In some aspects, the solid dosageform is a capsule.

In one embodiment of any of the methods described herein, themirdametinib, or a pharmaceutically acceptable salt thereof, isadministered as a monotherapy to treat the tumor or cancer. In someaspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in combination with another active ingredientand/or surgery to treat the tumor or cancer.

In one embodiment of any of the methods described herein, themirdametinib is mirdametinib free base.

In some aspects, a therapeutically effective amount of mirdametinib, ora pharmaceutically acceptable salt thereof, is administered.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in an amount of about 1 mg/m² to about 10 mg/m²per day based on mirdametinib free base, about 1.5 mg/m² to about 9.5mg/m² per day based on mirdametinib free base, about 2 mg/m² to about 9mg/m² per day based on mirdametinib free base, about 2.5 mg/m² to about8.5 mg/m² per day based on mirdametinib free base, about 3 mg/m² toabout 8 mg/m² per day based on mirdametinib free base, about 3.5 mg/m²to about 7.5 mg/m² per day based on mirdametinib free base, about 4mg/m² to about 7 mg/m² per day based on mirdametinib free base, about4.5 mg/m² to about 6.5 mg/m² per day based on mirdametinib free base, orabout 5 mg/m² to about 6 mg/m² per day based on mirdametinib free base.In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in an amount of about 1 mg/m² per day based onmirdametinib free base, about 1.5 mg/m² per day based on mirdametinibfree base, about 2 mg/m² per day based on mirdametinib free base, about2.5 mg/m² per day based on mirdametinib free base, about 3 mg/m² per daybased on mirdametinib free base, about 3.5 mg/m² per day based onmirdametinib free base, about 4 mg/m² per day based on mirdametinib freebase, about 4.5 mg/m² per day based on mirdametinib free base, about 5mg/m² per day based on mirdametinib free base, about 5.5 mg/m² per daybased on mirdametinib free base, about 6 mg/m² per day based onmirdametinib free base, about 6.5 mg/m² per day based on mirdametinibfree base, about 7 mg/m² per day based on mirdametinib free base, about7.5 mg/m² per day based on mirdametinib free base, about 8 mg/m² per daybased on mirdametinib free base, about 8.5 mg/m² per day based onmirdametinib free base, about 9 mg/m² per day based on mirdametinib freebase, about 9.5 mg/m² per day based on mirdametinib free base, or about10 mg/m² per day based on mirdametinib free base.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in an amount of about 1 mg to about 10 mg perday based on mirdametinib free base, about 1.5 mg to about 9.5 mg perday based on mirdametinib free base, about 2 mg to about 9 mg per daybased on mirdametinib free base, about 2.5 mg to about 8.5 mg per daybased on mirdametinib free base, about 3 mg to about 8 mg per day basedon mirdametinib free base, about 3.5 mg to about 7.5 mg per day based onmirdametinib free base, about 4 mg to about 7 mg per day based onmirdametinib free base, about 4.5 mg to about 6.5 mg per day based onmirdametinib free base, or about 5 mg to about 6 mg per day based onmirdametinib free base. In some aspects, the mirdametinib, or apharmaceutically acceptable salt thereof, is administered in an amountof about 1 mg per day based on mirdametinib free base, about 1.5 mg perday based on mirdametinib free base, about 2 mg per day based onmirdametinib free base, about 2.5 mg per day based on mirdametinib freebase, about 3 mg per day based on mirdametinib free base, about 3.5 mgper day based on mirdametinib free base, about 4 mg per day based onmirdametinib free base, about 4.5 mg per day based on mirdametinib freebase, about 5 mg per day based on mirdametinib free base, about 5.5 mgper day based on mirdametinib free base, about 6 mg per day based onmirdametinib free base, about 6.5 mg per day based on mirdametinib freebase, about 7 mg per day based on mirdametinib free base, about 7.5 mgper day based on mirdametinib free base, about 8 mg per day based onmirdametinib free base, about 8.5 mg per day based on mirdametinib freebase, about 9 mg per day based on mirdametinib free base, about 9.5 mgper day based on mirdametinib free base, or about 10 mg per day based onmirdametinib free base.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in a single dosage form comprising about 0.1mg/m² to about 10 mg/m² based on mirdametinib free base, about 0.5 mg/m²to about 9.5 mg/m² based on mirdametinib free base, about 1 mg/m² toabout 9 mg/m² based on mirdametinib free base, about 1.5 mg/m² to about8.5 mg/m² based on mirdametinib free base, about 2 mg/m² to about 8mg/m² based on mirdametinib free base, about 2.5 mg/m² to about 7.5mg/m² based on mirdametinib free base, about 3 mg/m² to about 7 mg/m²based on mirdametinib free base, about 3.5 mg/m² to about 6.5 mg/m²based on mirdametinib free base, about 4 mg/m² to about 6 mg/m² based onmirdametinib free base, or about 4.5 mg/m² to about 5.5 mg/m² based onmirdametinib free base. In some aspects, the mirdametinib, or apharmaceutically acceptable salt thereof, is administered in a singledosage form comprising about 0.1 mg/m² based on mirdametinib free base,about 0.2 mg/m² based on mirdametinib free base, about 0.3 mg/m² basedon mirdametinib free base, about 0.4 mg/m² based on mirdametinib freebase, about 0.5 mg/m² based on mirdametinib free base, about 1 mg/m²based on mirdametinib free base, about 1.5 mg/m² based on mirdametinibfree base, about 2 mg/m² based on mirdametinib free base, about 2.5mg/m² based on mirdametinib free base, about 3 mg/m² based onmirdametinib free base, about 3.5 mg/m² based on mirdametinib free base,about 4 mg/m² based on mirdametinib free base, about 4.5 mg/m² based onmirdametinib free base, about 5 mg/m² based on mirdametinib free base,about 5.5 mg/m² based on mirdametinib free base, about 6 mg/m² based onmirdametinib free base, about 6.5 mg/m² based on mirdametinib free base,about 7 mg/m² based on mirdametinib free base, about 7.5 mg/m² based onmirdametinib free base, about 8 mg/m² based on mirdametinib free base,about 8.5 mg/m² based on mirdametinib free base, about 9 mg/m² based onmirdametinib free base, about 9.5 mg/m² based on mirdametinib free base,or about 10 mg/m² based on mirdametinib free base.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in a single dosage form comprising about 0.1 mgto about 10 mg based on mirdametinib free base, about 0.5 mg to about9.5 mg based on mirdametinib free base, about 1 mg to about 9 mg basedon mirdametinib free base, about 1.5 mg to about 8.5 mg based onmirdametinib free base, about 2 mg to about 8 mg based on mirdametinibfree base, about 2.5 mg to about 7.5 mg based on mirdametinib free base,about 3 mg to about 7 mg based on mirdametinib free base, about 3.5 mgto about 6.5 mg based on mirdametinib free base, about 4 mg to about 6mg based on mirdametinib free base, or about 4.5 mg to about 5.5 mgbased on mirdametinib free base. In some aspects, the mirdametinib, or apharmaceutically acceptable salt thereof, is administered in a singledosage form comprising about 0.1 mg based on mirdametinib free base,about 0.2 mg based on mirdametinib free base, about 0.3 mg based onmirdametinib free base, about 0.4 mg based on mirdametinib free base,about 0.5 mg based on mirdametinib free base, about 1 mg based onmirdametinib free base, about 1.5 mg based on mirdametinib free base,about 2 mg based on mirdametinib free base, about 2.5 mg based onmirdametinib free base, about 3 mg based on mirdametinib free base,about 3.5 mg based on mirdametinib free base, about 4 mg based onmirdametinib free base, about 4.5 mg based on mirdametinib free base,about 5 mg based on mirdametinib free base, about 5.5 mg based onmirdametinib free base, about 6 mg based on mirdametinib free base,about 6.5 mg based on mirdametinib free base, about 7 mg based onmirdametinib free base, about 7.5 mg based on mirdametinib free base,about 8 mg based on mirdametinib free base, about 8.5 mg based onmirdametinib free base, about 9 mg based on mirdametinib free base,about 9.5 mg based on mirdametinib free base, or about 10 mg based onmirdametinib free base.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered one, two, three, or four times per day. In someaspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered once daily. In some aspects, the mirdametinib,or a pharmaceutically acceptable salt thereof, is administered twicedaily.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered twice daily in an amount of about 0.5 mg/m² toabout 10 mg/m² based on mirdametinib free base, about 1 mg/m² to about9.5 mg/m² based on mirdametinib free base, about 1.5 mg/m² to about 9mg/m² based on mirdametinib free base, about 2 mg/m² to about 8.5 mg/m²based on mirdametinib free base, about 2.5 mg/m² to about 8 mg/m² basedon mirdametinib free base, about 3 mg/m² to about 7.5 mg/m² based onmirdametinib free base, about 3.5 mg/m² to about 7 mg/m² based onmirdametinib free base, about 4 mg/m² to about 6.5 mg/m² based onmirdametinib free base, about 4.5 mg/m² to about 6 mg/m² based onmirdametinib free base, or about 5 mg/m² to about 6 mg/m² based onmirdametinib free base. In some aspects, the mirdametinib, or apharmaceutically acceptable salt thereof, is administered twice daily inan amount of about 0.5 mg/m² based on mirdametinib free base, about 1mg/m² based on mirdametinib free base, about 1.5 mg/m² based onmirdametinib free base, about 2 mg/m² based on mirdametinib free base,about 2.5 mg/m² based on mirdametinib free base, about 3 mg/m² based onmirdametinib free base, about 3.5 mg/m² based on mirdametinib free base,about 4 mg/m² based on mirdametinib free base, about 4.5 mg/m² based onmirdametinib free base, about 5 mg/m² based on mirdametinib free base,about 5.5 mg/m² based on mirdametinib free base, about 6 mg/m² based onmirdametinib free base, about 6.5 mg/m² based on mirdametinib free base,about 7 mg/m² based on mirdametinib free base, about 7.5 mg/m² based onmirdametinib free base, about 8 mg/m² based on mirdametinib free base,about 8.5 mg/m² based on mirdametinib free base, about 9 mg/m² based onmirdametinib free base, about 9.5 mg/m² based on mirdametinib free base,or about 10 mg/m² based on mirdametinib free base.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered twice daily in an amount of about 0.5 mg toabout 10 mg based on mirdametinib free base, about 1 mg to about 9.5 mgbased on mirdametinib free base, about 1.5 mg to about 9 mg based onmirdametinib free base, about 2 mg to about 8.5 mg based on mirdametinibfree base, about 2.5 mg to about 8 mg based on mirdametinib free base,about 3 mg to about 7.5 mg based on mirdametinib free base, about 3.5 mgto about 7 mg based on mirdametinib free base, about 4 mg to about 6.5mg based on mirdametinib free base, about 4.5 mg to about 6 mg based onmirdametinib free base, or about 5 mg to about 6 mg based onmirdametinib free base. In some aspects, the mirdametinib, or apharmaceutically acceptable salt thereof, is administered twice daily inan amount of about 0.5 mg based on mirdametinib free base, about 1 mgbased on mirdametinib free base, about 1.5 mg based on mirdametinib freebase, about 2 mg based on mirdametinib free base, about 2.5 mg based onmirdametinib free base, about 3 mg based on mirdametinib free base,about 3.5 mg based on mirdametinib free base, about 4 mg based onmirdametinib free base, about 4.5 mg based on mirdametinib free base,about 5 mg based on mirdametinib free base, about 5.5 mg based onmirdametinib free base, about 6 mg based on mirdametinib free base,about 6.5 mg based on mirdametinib free base, about 7 mg based onmirdametinib free base, about 7.5 mg based on mirdametinib free base,about 8 mg based on mirdametinib free base, about 8.5 mg based onmirdametinib free base, about 9 mg based on mirdametinib free base,about 9.5 mg based on mirdametinib free base, or about 10 mg based onmirdametinib free base.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in a total daily dose that does not exceedabout 10 mg/m² based on mirdametinib free base, about 9.5 mg/m² based onmirdametinib free base, about 9 mg/m² based on mirdametinib free base,about 8.5 mg/m² based on mirdametinib free base, about 8 mg/m² based onmirdametinib free base, about 7.5 mg/m² based on mirdametinib free base,about 7 mg/m² based on mirdametinib free base, about 6.5 mg/m² based onmirdametinib free base, about 6 mg/m² based on mirdametinib free base,about 5.5 mg/m² based on mirdametinib free base, about 5 mg/m² based onmirdametinib free base, about 4.5 mg/m² based on mirdametinib free base,about 4 mg/m² based on mirdametinib free base, about 3.5 mg/m² based onmirdametinib free base, about 3 mg/m² based on mirdametinib free base,about 2.5 mg/m² based on mirdametinib free base, about 2 mg/m² based onmirdametinib free base, or about 1.5 mg/m² based on mirdametinib freebase.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in a total daily dose that does not exceedabout 10 mg based on mirdametinib free base, about 9.5 mg based onmirdametinib free base, about 9 mg based on mirdametinib free base,about 8.5 mg based on mirdametinib free base, about 8 mg based onmirdametinib free base, about 7.5 mg based on mirdametinib free base,about 7 mg based on mirdametinib free base, about 6.5 mg based onmirdametinib free base, about 6 mg based on mirdametinib free base,about 5.5 mg based on mirdametinib free base, about 5 mg based onmirdametinib free base, about 4.5 mg based on mirdametinib free base,about 4 mg based on mirdametinib free base, about 3.5 mg based onmirdametinib free base, about 3 mg based on mirdametinib free base,about 2.5 mg based on mirdametinib free base, about 2 mg based onmirdametinib free base, or about 1.5 mg based on mirdametinib free base.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered as mirdametinib free base.

In some aspects, the mirdametinib free base is administered in an amountof about 1 mg/m² to about 10 mg/m² per day, about 1.5 mg/m² to about 9.5mg/m² per day, about 2 mg/m² to about 9 mg/m² per day, about 2.5 mg/m²to about 8.5 mg/m² per day, about 3 mg/m² to about 8 mg/m² per day,about 3.5 mg/m² to about 7.5 mg/m² per day, about 4 mg/m² to about 7mg/m² per day, about 4.5 mg/m² to about 6.5 mg/m² per day, or about 5mg/m² to about 6 mg/m² per day. In some aspects, the mirdametinib freebase is administered in an amount of about 1 mg/m² per day, about 1.5mg/m² per day, about 2 mg/m² per day, about 2.5 mg/m² per day, about 3mg/m² per day, about 3.5 mg/m² per day, about 4 mg/m² per day, about 4.5mg/m² per day, about 5 mg/m² per day, about 5.5 mg/m² per day, about 6mg/m² per day, about 6.5 mg/m² per day, about 7 mg/m² per day, about 7.5mg/m² per day, about 8 mg/m² per day, about 8.5 mg/m² per day, about 9mg/m² per day, about 9.5 mg/m² per day, or about 10 mg/m² per day.

In some aspects, the mirdametinib free base is administered in an amountof about 1 mg to about 10 mg per day, about 1.5 mg to about 9.5 mg perday, about 2 mg to about 9 mg per day, about 2.5 mg to about 8.5 mg perday, about 3 mg to about 8 mg per day, about 3.5 mg to about 7.5 mg perday, about 4 mg to about 7 mg per day, about 4.5 mg to about 6.5 mg perday, or about 5 mg to about 6 mg per day. In some aspects, themirdametinib free base is administered in an amount of about 1 mg perday, about 1.5 mg per day, about 2 mg per day, about 2.5 mg per day,about 3 mg per day, about 3.5 mg per day, about 4 mg per day, about 4.5mg per day, about 5 mg per day, about 5.5 mg per day, about 6 mg perday, about 6.5 mg per day, about 7 mg per day, about 7.5 mg per day,about 8 mg per day, about 8.5 mg per day, about 9 mg per day, about 9.5mg per day, or about 10 mg per day.

In some aspects, the mirdametinib free base is administered in a singledosage form comprising about 0.1 mg/m² to about 10 mg/m², about 0.5mg/m² to about 9.5 mg/m², about 1 mg/m² to about 9 mg/m², about 1.5mg/m² to about 8.5 mg/m², about 2 mg/m² to about 8 mg/m², about 2.5mg/m² to about 7.5 mg/m², about 3 mg/m² to about 7 mg/m², about 3.5mg/m² to about 6.5 mg/m², about 4 mg/m² to about 6 mg/m², or about 4.5mg/m² to about 5.5 mg/m². In some aspects, the mirdametinib free base isadministered in a single dosage form comprising about 0.1 mg/m², about0.2 mg/m², about 0.3 mg/m², about 0.4 mg/m², about 0.5 mg/m², about 1mg/m², about 1.5 mg/m², about 2 mg/m², about 2.5 mg/m², about 3 mg/m²,about 3.5 mg/m², about 4 mg/m², about 4.5 mg/m², about 5 mg/m², about5.5 mg/m², about 6 mg/m², about 6.5 mg/m², about 7 mg/m², about 7.5mg/m², about 8 mg/m², about 8.5 mg/m², about 9 mg/m², about 9.5 mg/m²,or about 10 mg/m².

In some aspects, the mirdametinib free base is administered in a singledosage form comprising about 0.1 mg to about 10 mg, about 0.5 mg toabout 9.5 mg, about 1 mg to about 9 mg, about 1.5 mg to about 8.5 mg,about 2 mg to about 8 mg, about 2.5 mg to about 7.5 mg, about 3 mg toabout 7 mg, about 3.5 mg to about 6.5 mg, about 4 mg to about 6 mg, orabout 4.5 mg to about 5.5 mg. In some aspects, the mirdametinib freebase is administered in a single dosage form comprising about 0.1 mg,about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1 mg,about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg,about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about9.5 mg, or about 10 mg.

In some aspects, the mirdametinib free base is administered one, two,three, or four times per day. In some aspects, the mirdametinib freebase is administered once daily. In some aspects, the mirdametinib freebase is administered twice daily.

In some aspects, the mirdametinib free base is administered twice dailyin an amount of about 0.5 mg/m² to about 10 mg/m², about 1 mg/m² toabout 9.5 mg/m², about 1.5 mg/m² to about 9 mg/m², about 2 mg/m² toabout 8.5 mg/m², about 2.5 mg/m² to about 8 mg/m², about 3 mg/m² toabout 7.5 mg/m², about 3.5 mg/m² to about 7 mg/m², about 4 mg/m² toabout 6.5 mg/m², about 4.5 mg/m² to about 6 mg/m², or about 5 mg/m² toabout 6 mg/m². In some aspects, the mirdametinib free base isadministered twice daily in an amount of about 0.5 mg/m², about 1 mg/m²,about 1.5 mg/m², about 2 mg/m², about 2.5 mg/m², about 3 mg/m², about3.5 mg/m², about 4 mg/m², about 4.5 mg/m², about 5 mg/m², about 5.5mg/m², about 6 mg/m², about 6.5 mg/m², about 7 mg/m², about 7.5 mg/m²,about 8 mg/m², about 8.5 mg/m², about 9 mg/m², about 9.5 mg/m², or about10 mg/m².

In some aspects, the mirdametinib free base is administered twice dailyin an amount of about 0.5 mg to about 10 mg, about 1 mg to about 9.5 mg,about 1.5 mg to about 9 mg, about 2 mg to about 8.5 mg, about 2.5 mg toabout 8 mg, about 3 mg to about 7.5 mg, about 3.5 mg to about 7 mg,about 4 mg to about 6.5 mg, about 4.5 mg to about 6 mg, or about 5 mg toabout 6 mg. In some aspects, the mirdametinib free base is administeredtwice daily in an amount of about 0.5 mg, about 1 mg, about 1.5 mg,about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg,about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, orabout 10 mg.

In some aspects, the mirdametinib free base is administered in a totaldaily dose that does not exceed about 10 mg/m², about 9.5 mg/m², about 9mg/m², about 8.5 mg/m², about 8 mg/m², about 7.5 mg/m², about 7 mg/m²,about 6.5 mg/m², about 6 mg/m², about 5.5 mg/m², about 5 mg/m², about4.5 mg/m², about 4 mg/m², about 3.5 mg/m², about 3 mg/m², about 2.5mg/m², about 2 mg/m², or about 1.5 mg/m².

In some aspects, the mirdametinib free base is administered in a totaldaily dose that does not exceed about 10 mg, about 9.5 mg, about 9 mg,about 8.5 mg, about 8 mg, about 7.5 mg, about 7 mg, about 6.5 mg, about6 mg, about 5.5 mg, about 5 mg, about 4.5 mg, about 4 mg, about 3.5 mg,about 3 mg, about 2.5 mg, about 2 mg, or about 1.5 mg.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, exhibits high blood-brain-barrier penetration.

In some aspects, the human patient has had no prior exposure to MEKinhibitors. In some aspects, the human patient has not responded toprior treatment to one or more MEK inhibitors.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered orally. In some aspects, the mirdametinib, or apharmaceutically acceptable salt thereof, is administered orally as asolid dosage form. In some aspects, the solid dosage form is a tablet orcapsule. In some aspects, the solid dosage form is a capsule. In someaspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is dispersible in a potable liquid or orodispersible in apatient's saliva. In one embodiment, the mirdametinib, or apharmaceutically acceptable salt thereof, is administered as adispersible formulation (such as a 0.5 mg or 1 mg mirdametinibdispersible tablet) as described in U.S. Pat. No. 11,571,402, which ishereby incorporated by reference.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered as a monotherapy to treat the tumor or cancer.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in combination with another active ingredientand/or surgery to treat the tumor or cancer.

III. Pharmaceutical Compositions

Yet another embodiment is an oral pharmaceutical composition comprising1.0 mg mirdametinib, where the composition provides, upon initial oraladministration to a human subject who has just initiated treatment withmirdametinib, an AUC_(0-tau) less than 400 ng·h/mL. In one embodiment,the composition provides, upon initial oral administration to a humansubject who has just initiated treatment with mirdametinib, anAUC_(0-tau) less than 375, 350, 325, 300, 275, 250, 225, 200, 175, 150,125, or 100 ng·h/mL.

Yet another embodiment is an oral pharmaceutical composition comprising1.0 mg mirdametinib, where the composition provides, upon initial oraladministration to a human subject who has just initiated treatment withmirdametinib, a C_(max) no more than 40 ng/mL. In one embodiment, thecomposition provides, upon initial oral administration to a humansubject who has just initiated treatment with mirdametinib, a C_(max) nomore than 38, 36, 34, 32, 30, or 28 ng/mL.

The oral pharmaceutical composition described herein may include one ormore pharmaceutically acceptable excipients. The oral pharmaceuticalcomposition may contain one or more diluents, disintegrants, lubricants,or any combination of any of the foregoing. In one embodiment, the oraldosage form comprises (a) about 0.1 w/w % to about 5 w/w % wt/wt % ofmirdametinib, (b) about 50 w/w % to about 98 w/w % of one or morediluents; (c) about 1 w/w % to about 10 w/w % of one or moredisintegrants; and (d) up to about 5 w/w % of one or more lubricants.

Suitable diluents include, but are not limited to, microcrystallinecellulose, lactose, mannitol, sorbitol, xylitol, sucrose, starch,pregelatinized starch, calcium sulfate, calcium carbonate, dibasiccalcium phosphate, and any combination of any of the foregoing. In oneembodiment, the oral dosage form includes the diluent microcrystallinecellulose.

Suitable disintegrants include, but are not limited to, croscarmellosesodium, sodium starch glycolate, crospovidone, microcrystallinecellulose, starch, pregelatinized starch, low substituted hydroxypropylcellulose, alginic acid, and any combination of any of the foregoing. Inone embodiment, the oral dosage form includes the disintegrantcroscarmellose sodium.

Suitable lubricants include, but are not limited to, magnesium stearate,stearic acid, calcium stearate, zinc stearate, beeswax, colloidalsilicon dioxide, hydrogenated vegetable oil, sodium stearyl fumarate,glycerol dibehenate, talc, and any combination of any of the foregoing.In one embodiment, the oral dosage form includes the lubricant magnesiumstearate.

The oral pharmaceutical composition can be a capsule, such as a hardgelatin capsule, or a tablet.

EXAMPLE Example 1: Phase I/II Evaluation of Single Agent Mirdametinib, aBrain-Penetrant MEK1/2 Inhibitor, for the Treatment of Children,Adolescents, and Young Adults with Brain Cancer

A multi-arm phase I/II trial of mirdametinib is to be conducted inpatients ≥2 and <25 years with brain cancer. Phase I requiresparticipants have no prior exposure to MEK inhibitors andrecurrent/progressive disease with biopsy-proven evidence of MAPKpathway activation. Three escalating dose levels (2 mg/m²/dose BID, 2.5mg/m²/dose BID and 3 mg/m²/dose BID) are planned using a rolling 6design.

The median age enrolled in the study is 10 years old (3-21). Nodose-limiting toxicities occur for all three dose levels. No MEK relatedretinopathy or cardiopathy is observed. No disease progressions areoccurred. Thus far, mirdametinib is well-tolerated and clinicallypromising when dosed continuously in patients with brain cancer.

Example 2: Phase 2b Trial of Mirdametinib in Adult and PediatricPatients with Neurofibromatosis Type 1 (NF1)-Associated InoperablePlexiform Neurofibromas (PNs) that are Progressing or CausingSignificant Morbidity

This study is to evaluate the efficacy, safety, and tolerability ofmirdametinib in participants ≥2 years of age with an inoperableNF1-associated plexiform neurofibromas (PNs) that is progressing and/orcausing significant morbidity.

Approximately 120 participants will be screened (assessed foreligibility as described below) to achieve approximately 100participants assigned to study treatment. Of these participants,approximately 50 will be ≥18 years of age and approximately 50 will be 2to 17 years of age.

Participants will be screened for up to 28 days prior to the first doseof study treatment mirdametinib. Study treatment will be administeredorally at a twice daily (BID) dose specified in the table below. Dosingwill be on a 28-day Cycle (4-week course) with a 3 week on/1 week offschedule. The treatment period will last for up to 24 Cycles followed bya 30-day Safety Follow-Up period.

Subject's BSA (m²) ≤0.69 0.7 to 1.04 1.05 to 1.49 ≥1.5 BID dose (mg) 1 23 4

A partial response is defined as PN decrease ≥20% compared to baselineusing centrally read Mill volumetric analysis.

Inclusion Criteria

Patients are eligible to be included in the study only if all of thefollowing criteria apply:

-   -   1. Participant must be ≥2 years of age inclusive, at the time of        signing the informed consent/assent.    -   2. Participants must have either the clinical diagnosis of NF1        using the National Institute of Health (NIH) Consensus        Conference criteria of at least 1 other diagnostic criterion        (Inclusion 2.1-2.6, see below) in addition to the presence of        PN, or have a constitutional NF1 mutation documented in a        Clinical Laboratory Improvement Amendments/College of American        Pathologists certified lab; additional criteria are as follows:        -   2.1. Six or more café-au-lait macules with a diameter >5 mm            in prepubertal and >15 mm in post-pubertal individuals,            respectively        -   2.2. Freckling in axilla or inguinal regions;        -   2.3. Optic glioma;        -   2.4. Two or more Lisch nodules;        -   2.5. A distinctive bony lesion (dysplasia of the sphenoid            bone or dysplasia of thinning of long bone cortex);        -   2.6. A first degree relative with NF1.    -   3. Participants must have PN that is progressive (Inclusion 3.1)        OR causing significant morbidity, such as (but not limited to)        head and neck lesions that are compromising the airway or great        vessels, brachial or lumbar plexus lesions that are causing        nerve compression and loss of function, lesions causing major        deformity or are significantly disfiguring (Inclusion 3.2),        lesions of the extremity that cause limb hypertrophy or loss of        function, and painful lesions. Participants with paraspinal PNs        will be eligible for this study. Histologic confirmation of        tumor is not necessary in the presence of consistent clinical        and radiographic findings but should be considered if malignant        degeneration of a PN is clinically suspected;        -   3.1. For participants enrolled for tumor progression,            progression is defined as:            -   3.1.1. A measurable increase in PN size (≥20% increase                in volume) documented by comparison of two Mill scans in                the time period of 12 months or less prior to first dose                of study treatment (mirdametinib).        -   3.2. For participants enrolled for a “major deformity” or            “significantly disfiguring” tumor, eligible tumors will be            limited to tumors of the head and neck or those on other            areas of the body that are unable to be concealed by            standard garments.    -   4. Participant has a PN that is deemed inoperable, defined as a        PN that cannot be completely surgically removed without risk for        substantial morbidity due to: encasement of or close proximity        to vital structures, invasiveness, or high vascularity of the        PN, or the participant refuses surgery. Participants who        previously underwent surgery for a PN will be eligible to enter        the study after the surgery, provided the PN was incompletely        resected and is evaluable by volumetric analysis.    -   5. Participants must have a target PN, defined as the clinically        most relevant PN, amenable to volumetric MM analysis. For the        purpose of this study, the target PN must be seen on at least 3        consecutive MM slices and the field of view must contain the        entire tumor of interest. As determined by central radiologic        review, a target PN must be analyzable by volumetrics, at least        5 mL in volume, and will be classified as “typical PN”, “nodular        PN”, or “solitary nodular PN” prior to first dose of study        treatment.    -   6. Participants ≥18 years of age must have a PN amenable to a        percutaneous biopsy and must be willing to undergo pre-, and on        treatment tumor biopsies providing fresh tumor tissue; there        should be no contraindication for serial biopsy; Patients 2 to        17 years of age should not undergo biopsy unless there is a        clinical indication to obtain fresh tumor tissue.    -   7. Participants ≥16 years of age must have a Karnofsky        performance level of ≥60%, and participants <16 years must have        a Lansky performance of ≥60%.    -   8. Participant has adequate organ and bone marrow function as        defined by the following screening laboratory values:        -   8.1. Absolute neutrophil count ≥1500 cells/μL;        -   8.2. Platelets ≥100×10³/μL;        -   8.3. Hemoglobin ≥9.5 g/dL;        -   8.4. Serum albumin ≥2.8 g/dL;        -   8.5. Calculated creatinine clearance at Screening ≥60 mL/min            (by Cockcroft-Gault formula) OR a normal serum creatinine            based on age described in the table below.

Maximum Serum Age (years) Creatinine (mg/dL)  ≤5 0.8  >5 and ≤10 1.0 >10and ≤15 1.2 >15 1.5

-   -   9. Participant has the ability to swallow capsules whole.    -   10. Participant is willing and able to comply with all aspects        of the protocol.    -   11. Participant must weigh at least 10 kg, inclusive, at the        time of signing the informed consent/assent.    -   12. Participant must have a body surface area (BSA) of at least        0.4 m² (inclusive) calculated using the Du Bois formula        (BSA=0.007184×w^(0.425)×H^(0.725)).    -   13. Male or Female    -   Contraceptive use by men or women should be consistent with        local regulations regarding the methods of contraception for        those participating in clinical studies.        -   a. Male participants:        -   Male participants are eligible to participate if they agree            to the following during the treatment period and for at            least 90 days after the last dose of study treatment:            -   Refrain from donating sperm            -   PLUS either:            -   Be abstinent from heterosexual intercourse as their                preferred and usual lifestyle (abstinent on a long term                and persistent basis) and agree to remain abstinent OR            -   Must agree to use a male condom when having sexual                intercourse with a woman of child bearing potential                (WOCBP).        -   b. Female participants:        -   Female participants are eligible to participate if they are            not pregnant or breastfeeding, and at least one of the            following conditions applies:            -   Is not a woman of childbearing potential                -   OR            -   Is a WOCBP and using a contraceptive method that is                highly effective (with a failure rate of <1% per year),                preferably with low user dependency, during the                treatment period and for at least 30 days after the last                dose of study treatment and agrees not to donate eggs                (ova, oocytes) for the purpose of reproduction during                the study and for a period of 90 days.                -   A WOCBP must have a negative serum pregnancy test                    result at Screening and a negative urine pregnancy                    test result at the Baseline visit prior to the first                    dose of study treatment.                    Exclusion Criteria

Participants are excluded from the study if any of the followingcriteria apply:

-   -   1. Participant has a Screening alanine transaminase (ALT) value        of >2.0×upper limit of normal (ULN);    -   2. Participant has a Screening total bilirubin value of >1.5×ULN        (isolated bilirubin >1.5×ULN is acceptable if bilirubin is        fractionated and direct bilirubin <35%);    -   3. Participant has a history of malignancy associated        hypercalcemia;    -   4. Participant has an active parathyroid disorder,        hyperphosphatemia at Screening (serum phosphorus >1×ULN), and/or        serum calcium (mg/dL)×serum phosphorus (mg/dL) product >70 at        Screening.    -   5. Any clinically significant active or known history of liver        disease, or known hepatic or biliary abnormalities (with the        exception of Gilbert's syndrome or asymptomatic gallstones);        -   5.1 Hepatitis serology and viral load will be tested at            Screening. Patients who are hepatitis B surface antigen            (HBsAg) positive or hepatitis C virus (HCV) antibody            positive at Screening must not be enrolled until further            definite testing with hepatitis B virus (HBV)            deoxyribonucleic acid (DNA) titers is <500 IU/mL or HCV            ribonucleic acid (RNA) polymerase chain reaction test is            negative;    -   6. Lymphoma, leukemia, or any malignancy (including malignant        glioma or malignant peripheral nerve sheath tumor (MPNST))        within the past 5 years except for basal cell or squamous        epithelial carcinomas of the skin that have been resected with        no evidence of metastatic disease for 3 years;    -   7. Breast cancer within the past 10 years;    -   8. Participants with evidence of an active optic glioma or other        low-grade glioma, requiring treatment with chemotherapy or        radiation therapy. Participants not requiring treatment are        eligible. Ophthalmological findings secondary to long-standing        optic pathway glioma (such as visual loss, optic nerve pallor or        strabismus) or long-standing orbito-temporal PN (such as visual        loss, strabismus) will not be considered a significant        abnormality for the purposes of the study;    -   9. Participant has abnormal QT interval corrected by        Fridericia's formula (>450 msec for male participants, >470 msec        for female participants, or >480 msec for participants with        bundle branch block) after electrolytes have been corrected        (triplicate ECG readings taken 2 to 3 minutes apart and        averaged) at Screening;    -   10. Participant has experienced any of the following within 6        months (24 weeks) of signing informed consent/assent: clinically        significant cardiac disease, myocardial infarction,        severe/unstable angina, coronary/peripheral artery bypass graft,        cerebrovascular accident, transient ischemic attack, or        symptomatic pulmonary embolism;    -   11. Participant has ever had a recorded left ventricular        ejection fraction (LVEF)<55% as assessed by echocardiogram, OR        has a history of congestive heart failure;    -   12. Participant has a history of, or evidence of, retinal        pathology on ophthalmologic examination that is considered a        risk factor for central serous retinopathy, retinal vein        occlusion (RVO), or neovascular macular degeneration.        Participants will be excluded from study participation if they        currently are known to have any of the following risk factors        for RVO:        -   12.1 Intraocular pressure ≥21 mmHg;        -   12.2 Serum cholesterol >300 mg/dL;        -   12.3 Serum triglycerides >300 mg/dL;        -   12.4 Hyperglycemia (fasting blood glucose >125 mg/dL or            random blood glucose >200 mg/dL);        -   12.5 Age specific hypertension            -   i. Participants ≥13 years of age with a blood pressure                ≥140/90 mm Hg            -   ii. Participants ≤12 years of age with a blood pressure                ≥95th percentile for age+12 mmHg;    -   13. Participant has a history of glaucoma;    -   14. Participant has a history of a positive human        immunodeficiency virus (HIV) antibody test;    -   15. Participant has a known malabsorption syndrome or        preexisting gastrointestinal conditions that may impair        absorption of mirdametinib (e.g., gastric bypass, lap band, or        other gastric procedures). Delivery of mirdametinib via        nasogastric tube or gastrostomy tube is not allowed.    -   16. Participant has received NF1 PN-targeted therapy (e.g., MEK        inhibitors, farnesyltransferase inhibitors, kinase inhibitors,        etc.) within 28 days of first dose of study treatment (or 5.5        half-lives, whichever is longer). If participant enrolls with        progression and no associated morbidities, NF1-targeted therapy        must not be administered after the observed progression        (Inclusion Criterion 3.1.1). All toxicities from prior therapy        must resolve to ≤Grade 1 or Baseline;    -   17. Participant previously received or is currently receiving        therapy with mirdametinib;    -   18. Participant is receiving systemic or ocular glucocorticoid        therapy (with the exception of participants with endocrine        deficiencies who are allowed to receive physiologic or stress        doses of steroids, if necessary) within 14 days prior to first        dose of study treatment;    -   19. Participant has received radiation therapy within the 6        months prior to signing of informed consent/assent. Participants        who have received radiation to the orbit at any time are        excluded;    -   20. Current enrollment or past participation in any other        clinical study (excluding observational studies) within 28 days        of signing of informed consent/assent;    -   21. Participant is unable to tolerate Mill or for whom Mill is        contraindicated;    -   22. Tumor is not able to be reliably evaluated by Mill        volumetric analysis;    -   23. Sensitivity to the study treatment, or components thereof,        or drug or other allergy that, in the opinion of the        investigator or medical monitor, contraindicates participation        in the study;    -   24. Participant with active bacterial, fungal, or viral        infection including but not limited to the use of antibiotics,        antifungals, or antiviral agents at the time of screening;    -   25. Underlying medical conditions, laboratory abnormality, or        alcohol or drug abuse or dependence that, in the investigator's        opinion, will be unfavorable for the administration of study        treatment or affect the explanation of drug toxicity or adverse        events; or insufficient compliance during the study according to        investigator's judgement; or    -   26. Participant has experienced other severe acute or chronic        medical or psychiatric conditions, including recent (within 1        year of signing informed consent/assent) or active suicidal        ideation or behavior, or a laboratory abnormality that may        increase the risk associated with study participation or study        treatment administration or may interfere with the        interpretation of study results and, in the judgment of the        Investigator, would make the participant inappropriate for entry        into this study.        Supportive Care

Dermatologic Adverse Events:

The use of medications for the supportive care of rash is permitted.Early initiation of treatment for rashes is strongly recommended tominimize the duration and severity of the adverse event.

Acneiform rash: Pustular rash may be treated with topical clindamycingel or lotion applied BID. In severe cases, semisynthetic oraltetracyclines such as doxycycline or minocycline may also be useful forolder children, adolescents, and adults, but should be avoided inchildren younger than 8 years old because of risk to tooth development.

Eczematous rash/xerosis: Eczematous/dry skin rash and other macular(non-acneiform) rash should be treated with a moisturizer such as Ceraveor Eucerin or another equivalent product. A low potency topical steroidsuch as betamethasone valerate lotion (0.05%), desonide cream (0.05%),fluocinolone acetonide solution (0.01%), dexamethasone sodium phosphatecream (0.1%), hydrocortisone acetate cream (1%), methylprednisoloneacetate cream (0.25%) or equivalent may also be used if symptomatic.

Ketoconazole shampoo should be used for any rash involving the scalp.

Paronychia: Paronychia if acute and non-surgical (i.e., no fluctuancesuggesting an abscess) can resolve with warm soaks only applied 3 to 4times daily. If there is extensive redness suggesting cellulitis, OR ifthere is non-surgical paronychia but the participant is a diabetic or isimmuno-compromised, then an oral antibiotic that covers Staphylococcusaureus should be started. The choice of antibiotics includes aStaphylococcus aureus covering penicillin/clindamycin/first generationcephalosporin/Augmentin (amoxicillin and clavulanate).

If an abscess develops, surgical treatment with incision and drainagewith or without debridement should be done. Any infectious organismsidentified should be treated accordingly. If the participant hasdiabetes or is immune compromised, oral antibiotics ensuring coveragefor Staphylococcal aureus (see above) should be started prior to aculture and sensitivity report. Once culture report is obtained, theantibiotic therapy should be adjusted as appropriate.

Prohibited or Restricted Concomitant Medications/Treatments

-   -   Prior use of mirdametinib is prohibited.    -   Alternative therapy for the treatment of PNs (e.g. MEK        inhibitors, farnesyltransferase inhibitors, kinase inhibitors,        etc.) within 28 days (or 5.5 half-lives, whichever is longer) of        first dose of study treatment and throughout the treatment        period is prohibited. If participant enrolls with progression        and no associated morbidities, NF1-targeted therapy must not be        administered after the observed progression (Inclusion Criterion        3.1.1)    -   Medical treatment (e.g. chemotherapy, biologic therapy,        radiation therapy) directed towards any NF1-related tumor such        as optic pathway glioma is prohibited throughout the treatment        period.    -   The use of chronic systemic or ocular glucocorticoid therapy is        prohibited within the 14 days prior to first dose of study        treatment and throughout the treatment period (with the        exception of participants with endocrine deficiencies who are        allowed to receive physiologic or stress doses of steroids, if        necessary). In addition, corticosteroids are permissible as        premedication for blood product transfusions, or as treatment        for an acute allergic reaction or bronchospasm.

All publications, patents, and patent applications mentioned in thisspecification are incorporated herein by reference in their entirety tothe same extent as if each individual publication, patent, or patentapplication was specifically and individually indicated to beincorporated by reference in its entirety. Where a term in the presentapplication is found to be defined differently in a documentincorporated herein by reference, the definition provided herein is toserve as the definition for the term.

While the invention has been described in connection with specificaspects thereof, it will be understood that invention is capable offurther modifications and this application is intended to cover anyvariations, uses, or adaptations following, in general, the principlesand including such departures from the present disclosure that comewithin known or customary practice within the art to which the inventionpertains and can be applied to the essential features hereinbefore setforth, and follows in the scope of the claimed.

What is claimed:
 1. A method of treating a human patient 2 years orolder who has neurofibromatosis type 1 (NF1) associated inoperableplexiform neurofibromas (PN) comprising orally administering aneffective amount of mirdametinib to the patient, wherein an amount ofmirdametinib is administered on the first day of treatment to provide anAUC_(0-tau) less than 300 ng·h/mL.
 2. The method of claim 1, wherein thepatient has symptomatic, inoperable plexiform neurofibromas.
 3. A methodof treating a human patient 2 years or older who has neurofibromatosistype 1 (NF1) associated inoperable plexiform neurofibromas (PN) that isprogressing or causing significant morbidity comprising orallyadministering an effective amount of mirdametinib to the patient,wherein an amount of mirdametinib is administered on the first day oftreatment to provide an AUC_(0-tau) less than 300 ng·h/mL.
 4. The methodof claim 1, wherein an amount of mirdametinib is administered on thefirst day of treatment to provide an AUC_(0-tau) less than 200 ng·h/mL.5. The method of claim 1, wherein an amount of mirdametinib isadministered on the first day of treatment to provide an AUC_(0-tau)less than 100 ng·h/mL.
 6. The method of claim 1, wherein the patient hasprogressive PN.
 7. The method of claim 1, wherein the patient has PNsthat cause significant morbidity.
 8. The method of claim 1, wherein thepatient has head and neck lesions that are compromising the airway orgreat vessels, brachial or lumbar plexus lesions that are causing nervecompression and loss of function, lesions causing major deformity or aresignificantly disfiguring, lesions of the extremity that cause limbhypertrophy or loss of function, or painful lesions.
 9. The method ofclaim 8, wherein the lesions causing major deformity or aresignificantly disfiguring are tumors of the head and neck or those onother areas of the body that are unable to be concealed by standardgarments.
 10. The method of claim 1, wherein the patient has paraspinallesions.
 11. The method of claim 1, wherein the patient has the clinicaldiagnosis of NF1 using the NIH Consensus Conference and one or more ofthe following: (a) six or more café-au-lait macules with a diameter >5mm in prepubertal and >15 mm in post-pubertal individuals; (b) frecklingin axilla or inguinal regions; (c) optic glioma; (d) two or more Lischnodules; (e) a distinctive bony lesion (dysplasia of the sphenoid boneor dysplasia of thinning of long bone cortex); and (f) a first degreerelative with NF1.
 12. The method of claim 1, wherein the patient has aconstitutional NF1 mutation documented in a Clinical LaboratoryImprovement Amendments/College of American Pathologists certified lab.13. The method of claim 1, wherein the patient either (a) has a parentdiagnosed with NF1 and one or more criteria of (1) through (7) or (b)does not have a parent diagnosed with NF1 but has two or more criteriaof (1) through (7): (1) six or more café-au-lait macules over 5 mm ingreatest diameter in prepubertal individuals and over 15 mm in greatestdiameter in post-pubertal individuals; (2) freckling in the axillary oringuinal region; (3) two or more neurofibromas of any type or oneplexiform neurofibroma (4) optic pathway glioma; (5) two or more irisLisch nodules identified by slit lamp examination or two or morechoroidal abnormalities (defined as bright, patchy nodules imaged byoptical coherence tomography (OCT)/near-infrared reflectance (NIR)imaging; (6) a distinctive osseus lesion (such as sphenoid dysplasia,anterolateral bowing of the tibia, or pseudarthrosis of a long bone);and (7) a heterozygous pathogenic NF1 variant with a variant allelefraction of 50% in apparently normal tissue such as white blood cells.14. The method of claim 1, wherein (a) for a patient having a bodysurface area no more than 0.69 m², the patient is initially administered1 mg mirdametinib twice daily, (b) for a patient having a body surfacearea of 0.7 to 1.04 m², the patient is initially administered 2 mgmirdametinib twice daily, (c) for a patient having a body surface areaof 1.05 to 1.49 m², the patient is initially administered 3 mgmirdametinib twice daily, and (d) for a patient having a body surfacearea of at least 1.5 m², the patient is initially administered 4 mgmirdametinib twice daily.
 15. The method of claim 1, wherein the maximumdaily dose is 4 mg mirdametinib twice daily.
 16. The method of claim 13,wherein over each four week period, the mirdametinib is administered forthe first three weeks and discontinued for the last one week.
 17. Themethod of claim 1, wherein the patient has at least a 20% reduction inplexiform neurofibroma volume as determined by volumetric magneticresonance imaging analysis following treatment with mirdametinib. 18.The method of claim 1, wherein the treatment results in decreased painintensity.
 19. The method of claim 1, wherein the treatment results indecreased pain interference.
 20. The method of claim 13, wherein thedose administered is reduced due to an adverse event, wherein the doseis reduced as follows: (a) if the dose at the time of the event is 1 mgmirdametinib twice daily, then the reduced daily dose is 1 mgadministered in the morning only; (b) if the dose at the time of theevent is 2 mg mirdametinib twice daily, then the reduced daily dose is 2mg administered in the morning and 1 mg administered in the afternoon orevening; (c) if the dose at the time of the event is 3 mg mirdametinibtwice daily, then the reduced daily dose is 2 mg administered twicedaily; and (d) if the dose at the time of the event is 4 mg mirdametinibtwice daily, then the reduced daily dose is 3 mg administered twicedaily.
 21. The method of claim 20, wherein the adverse event resultingin the dose reduction is acneiform.
 22. The method of claim 21, wherein,during treatment, the patient is topically administered clindamycin totreat the acneiform.
 23. The method of claim 1, wherein the patient is 2to 15 years of age.
 24. A method of treating a human patient 2 years orolder who has neurofibromatosis type 1 (NF1) associated inoperableplexiform neurofibromas (PN) comprising orally administering on thefirst day of treatment 1 mg of mirdametinib twice daily to the patientto achieve an AUC_(0-tau) less than 300 ng·h/mL.
 25. The method of claim1, wherein the method further comprises prior to treatment (i)determining whether to select mirdametinib as a treatment for thepatient, and (ii) selecting mirdametinib as a treatment for the patientat least partially based on its objective response rate, where theobjective response rate is defined as at least a 20% decrease in tumorsize using centrally read MRI volumetric analysis.
 26. The method ofclaim 25, wherein in step (i), mirdametinib is selected based on aresponse rate of at least 70%.